This second submission should provide support that demonstrates no meaningful clinical difference between CT-P10 and US-licensed Rituxan.

/by

Committee: Oncologic Drugs

Indication: The treatment of adult patients with (1) relapsed or refractory, low-grade or follicular, CD20-positive, B- cell Non-Hodgkin's Lymphoma (NHL) as a single agent; (2) previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to CT-P10 in combination with chemotherapy, as single- agent maintenance therapy; and (3) non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone.

Drug/Device: CT-P10

Sponsor: Genentech & Celltrion

Links:

Relevant Question: 

Does this second submission provide support that demonstrates no meaningful clinical difference between CT-P10 and US-licensed Rituxan?

Unique Challenges:

This AdCom meeting covered biologics license application (BLA) 761088 for CT-P10. The first submission of this biosimilar product was in April 2017 and the submission was rejected. This second submission should provide support that demonstrates no meaningful clinical difference between CT-P10 and US-licensed Rituxan.

 

From a clinical and statistical perspective, the safety and efficacy results of clinical study CT-P10 3.3 in the first submission were not satisfied with FDA definition for biosimilarity. First of all, the non-inferiority study design in CT-P10 3.3 was not considered adequate to preclude the superiority of CT-P10, although inferiority was met. In study CT-P10 3.3, the lower bound of 90% CI of difference for the overall response rate (ORR) was greater than the proposed inferiority margin, while the upper bound of difference does not rule out superiority, which may be due to the fact that the study was underpowered.

 

The second consideration was that the sensitivity of the Advanced Follicular Lymphoma (AFL) population in CT-P10 3.3 could have had an influence on detecting differences between products due to the presence of concurrent background chemotherapy, that is, concurrent treatment with CVP. Taking into account the uncertainty, a mono treatment design should be developed to rule out the possibility and uncertainty of CVP influence on the clinical outcomes of CT-P10.

 

Based on these clinical and statistical concerns, a new clinical study CT-P10 3.4 was conducted in the population with Low Tumor Burden Follicular Lymphoma (LTBFL), without concurrent treatment of CVP to avoid the influence of chemotherapy.

 

It was an equivalent design with a randomized, parallel group, active-controlled, double blind study to compare clinical outcomes, overall response rates (ORR) and safety between CT-P10 and US-Licensed Rituxan for the patients with LTBFL. The parallel groups were designed with mono treatment (i.e., one arm was injected with CT-P10, another one with Rituxan).

 

The equivalence margin was determined by historical treatment efficacy of Rituxan, which is conservatively estimated at 75%. By applying a 77% preservation rate, the equivalence margin was proposed as  +/- 17%.

 

As part of the study design, sample size was initially determined based on primary endpoint (ORR), with a 91% statistical power for equivalence in ORR up to 7 months. Sample size was reassessed to account for actual dropout rate and the observed ORR to achieve an adequate statistical power for the primary endpoint (at least 80% power in the PP population).

**Note: On November 28, 2018 the FDA  announced its approval of this first biosimilar for treatment of adult patients with non-Hodgkin's lymphoma